Abstract
Objectives
Vitamin E is an essential micronutrient and critical human antioxidant that has been tested for cancer and cardiovascular preventative effects for decades with conflicting results. For example, prostate cancer incidence was reduced by a low-dose vitamin E supplement in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, but the findings were not replicated by high-dose vitamin E trials such as the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The present investigation examined the serum metabolomic responses to low- and high-dose vitamin E supplementation in order to gain biological insight into the divergent trial outcomes.
Methods
We examined baseline and on-study serum samples for 154 men randomly assigned to receive 400 IU vitamin E (as alpha-tocopheryl acetate; ATA) or placebo daily in the Vitamin E Atherosclerosis Prevention Study (VEAPS), and 100 men administered 50 IU ATA or placebo daily in the ATBC Study. Over 970 known metabolites were identified using an ultrahigh-performance LC-MS/MS platform. Linear regression models estimated the change in serum metabolites of men supplemented with vitamin E to those assigned to placebo in VEAPS compared with ATBC.
Results
Serum alpha-carboxyethyl hydrochroman (CEHC) sulfate, alpha-tocopherol, and beta-/gamma-tocopherol were significantly altered by supplementation with ATA in both the VEAPS and ATBC trials (all P-values ≤ 5.1 × 10−5, the Bonferroni multiple-comparisons corrected statistical threshold). Serum C22 lactone sulfate was also significantly decreased in response to the high-dose vitamin E supplement in VEAPS (β = −0.70, P-value = 8.1 × 10−6), but not altered in the low-dose ATBC trial (β = −0.17, P-value = 0.4). Additionally, changes in several androgenic steroid metabolites were strongly related to the vitamin E supplement-associated change in C22 lactone sulfate only in the high-dose VEAPS trial.
Conclusions
We found evidence of a dose-dependent vitamin E supplementation effect on a novel C22 lactone sulfate compound as well as several androgenic steroids that may have relevance to previous controlled trial findings for prostate cancer.
Funding Sources
This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, U.S. Public Health Service, Department of Health and Human Services.
Serum Metabolomic Response to Low and High Dose Vitamin E Supplementation in Two Randomized Controlled Trials